Prediction of Noncompetitive Inhibitor Binding Mode Reveals Promising Site for Allosteric Modulation of Falcipain-2

2019 ◽  
Vol 123 (34) ◽  
pp. 7327-7342 ◽  
Author(s):  
Jorge Enrique Hernández González ◽  
Lilian Hernández Alvarez ◽  
Pedro Geraldo Pascutti ◽  
Vitor B. P. Leite
Keyword(s):  
Binding Mode ◽  
Allosteric Modulation ◽  
Inhibitor Binding ◽  
Noncompetitive Inhibitor

scholarly journals DFG-1 Residue Controls Inhibitor Binding Mode and Affinity, Providing a Basis for Rational Design of Kinase Inhibitor Selectivity

2020 ◽  
Vol 63 (18) ◽  
pp. 10224-10234 ◽  
Author(s):  
Martin Schröder ◽  
Alex N. Bullock ◽  
Oleg Fedorov ◽  
Franz Bracher ◽  
Apirat Chaikuad ◽  
...  
Keyword(s):  
Rational Design ◽  
Kinase Inhibitor ◽  
Binding Mode ◽  
Inhibitor Binding ◽  
Inhibitor Selectivity

2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode

2010 ◽  
Vol 20 (1) ◽  
pp. 330-333 ◽  
Author(s):  
Maria A. Argiriadi ◽  
Anna M. Ericsson ◽  
Christopher M. Harris ◽  
David L. Banach ◽  
David W. Borhani ◽  
...  
Keyword(s):  
Binding Mode ◽  
Inhibitor Binding

scholarly journals Inhibitor binding mode and allosteric regulation of Na+-glucose symporters

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Paola Bisignano ◽  
Chiara Ghezzi ◽  
Hyunil Jo ◽  
Nicholas F. Polizzi ◽  
Thorsten Althoff ◽  
...  
Keyword(s):  
Allosteric Regulation ◽  
Binding Mode ◽  
Inhibitor Binding

scholarly journals Inhibitor-binding mode of homobelactosin C to proteasomes: New insights into class I MHC ligand generation

2006 ◽  
Vol 103 (12) ◽  
pp. 4576-4579 ◽  
Author(s):  
M. Groll ◽  
O. V. Larionov ◽  
R. Huber ◽  
A. de Meijere
Keyword(s):  
Binding Mode ◽  
Class I ◽  
Inhibitor Binding ◽  
Class I Mhc

scholarly journals DFG-1 residue controls inhibitor binding mode and affinity providing a basis for rational design of kinase inhibitor selectivity

2020 ◽  
Author(s):  
Martin Schröder ◽  
Alex N. Bullock ◽  
Oleg Federov ◽  
Franz Bracher ◽  
Apirat Chaikuad ◽  
...  
Keyword(s):  
Rational Design ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Binding Mode ◽  
Selectivity Filter ◽  
Binding Modes ◽  
Selective Inhibitors ◽  
Inhibitor Binding ◽  
Binding Pockets ◽  
Inhibitor Selectivity

ABSTRACTSelectivity remains a challenge for ATP-mimetic kinase inhibitors, an issue that may be overcome by targeting unique residues or binding pockets. However, to date only few strategies have been developed. Here we identify that bulky residues located N-terminal to the DFG motif (DFG-1) represent an opportunity for designing highly selective inhibitors with unexpected binding modes. We demonstrate that several diverse inhibitors exerted selective, non-canonical binding modes that exclusively target large hydrophobic DFG-1 residues present in many kinases including PIM, CK1, DAPK and CLK. Using the CLK family as a model, structural and biochemical data revealed that the DFG-1 valine controlled a non-canonical binding mode in CLK1, providing a rational for selectivity over the closely-related CLK3 which harbors a smaller DFG-1 alanine. Our data suggests that targeting the restricted back pocket in the small fraction of kinases that harbor bulky DFG-1 residues offers a versatile selectivity filter for inhibitor design.

Tn5 transposase as a useful platform to simulate HIV-1 integrase inhibitor binding mode

2007 ◽  
Vol 363 (3) ◽  
pp. 554-560 ◽  
Author(s):  
Maria Letizia Barreca ◽  
Francesco Ortuso ◽  
Nunzio Iraci ◽  
Laura De Luca ◽  
Stefano Alcaro ◽  
...  
Keyword(s):  
Integrase Inhibitor ◽  
Binding Mode ◽  
Inhibitor Binding ◽  
Tn5 Transposase ◽  
Hiv 1

scholarly journals Escherichia coliTopoisomerase IV E Subunit and an Inhibitor Binding Mode Revealed by NMR Spectroscopy

2016 ◽  
Vol 291 (34) ◽  
pp. 17743-17753 ◽  
Author(s):  
Yan Li ◽  
Ying Lei Wong ◽  
Fui Mee Ng ◽  
Boping Liu ◽  
Yun Xuan Wong ◽  
...  
Keyword(s):  
Nmr Spectroscopy ◽  
Binding Mode ◽  
Inhibitor Binding

scholarly journals Structural basis of main proteases of coronavirus bound to drug candidate PF-07321332

2021 ◽  
Author(s):  
Jian Li ◽  
Cheng Lin ◽  
Xuelan Zhou ◽  
Fanglin Zhong ◽  
Pei Zeng ◽  
...  
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Binding Mode ◽  
Structural Basis ◽  
Drug Candidate ◽  
Structural Determinants ◽  
Inhibitor Binding ◽  
Mechanism Of Inhibition ◽  
Main Protease ◽  
Multiple Variants

The high mutation rate of COVID-19 and the prevalence of multiple variants strongly support the need for pharmacological options to complement vaccine strategies. One region that appears highly conserved among different genus of coronaviruses is the substrate binding site of the main protease (Mpro or 3CLpro), making it an attractive target for the development of broad-spectrum drugs for multiple coronaviruses. PF-07321332 developed by Pfizer is the first orally administered inhibitor targeting the main protease of SARS-CoV-2, which also has shown potency against other coronaviruses. Here we report three crystal structures of main protease of SARS-CoV-2, SARS-CoV and MERS-CoV bound to the inhibitor PF-07321332. The structures reveal a ligand-binding site that is conserved among SARS-CoV-2, SARS-CoV and MERS-CoV, providing insights into the mechanism of inhibition of viral replication. The long and narrow cavity in the cleft between domains I and II of main protease harbors multiple inhibitor binding sites, where PF-07321332 occupies subsites S1, S2 and S4 and appears more restricted compared with other inhibitors. A detailed analysis of these structures illuminated key structural determinants essential for inhibition and elucidated the binding mode of action of main proteases from different coronaviruses. Given the importance of main protease for the treatment of SARS-CoV-2 infection, insights derived from this study should accelerate the design of safer and more effective antivirals.

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